The invention relates to the use of compounds in combination with high pressure impulse transients for the treatment of diseases of cell proliferation including both neoplasms and inflammatory diseases.
Photodynamic therapy is the use of light in combination with chemotherapy for the treatment of diseases of cell proliferation. The use of a cytotoxic drug causes cell death to the target tissue when exposed to light (Henderson and Dougherty, Photochem-Photobiol. 55:145-57, 1992; Wieman and Fingar, Surg. Clin. North. Am. 72:609-22, 1992). The target localization of the chemotherapeutic compound provides the first level of selectivity. The drug need not be localized with absolute specificity to the target tissue because of the activation by light; rather, it need only localize relative to the surrounding tissue. The drug must be non-toxic in the dark but should become toxic in the presence of light. The toxicity is generally, but not always, mediated by oxygen radicals. The drugs can have single functional units as in rhodamine dyes (Shea et al., Cancer Res. 49:3961-5, 1989), or the drugs can have separate units as in antibody-chromophore conjugates (Oseroff et al., Proc. Natl. Acad. Sci. U.S.A. 83:8744-8, 1986). The second level of localization comes from the distribution of activating light. The area of the body to be treated is illuminated to activate the drug in the specific region. The drug is not activated in the non-illuminated areas of the body even if it has accumulated in these locations and, thus, does not cause significant morbidity. Major current limitations of this technology include the limited light penetration of the tissue, the light dosimetry, and the choice of wavelengths of light is limited by the absorption of the chromophore.
The interaction of laser radiation with tissue can lead to generation of pressure waves (e.g., Cleary, Laser Applications in Biology and Medicine 3:175-219, 1977). Depending upon the type of interaction, pressure waves can be either acoustic waves, i.e., low pressure waves propagating with the speed of sound, or shock waves, i.e., high pressure waves propagating at supersonic speed (e.g., Hutchins, Physical Acoustics 18:21-123, 1988). The latter are generated when the absorption of laser radiation is followed by a rapid phase change of the medium such as evaporation or formation of plasma. The salient feature of a shock wave is a fast rise which for all practical purposes amounts to a discontinuity in pressure, density, particle velocity (the displacement velocity behind the shock front) and internal energy (e.g., Duval and Fowles, High Pressure Physics and Chemistry 2:201-291, 1963). In water, the rise time of a shock wave, up to 100 kbar, is of the order of a picosecond which corresponds to a shock front thickness of 2-5 nm (Harris and Presles, J. Chem. Phys. 77:5157-5164, 1982).
The effects of laser-induced pressure waves on tissue have been the subject of extensive research, especially at these effects pertain to laser applications in ophthalmology (e.g., Richardson et al., Ophthalmol. 92:1387-1395, 1985; Zysset et al., Lasers Surg. Med. 9:193-204, 1989; Vogel et al., IEEE J. Quant. Electr. QE 26:2240-2260, 1990).
Ara et al. (Lasers Surg. Med. 10:52-59 (1990)) have studied the effects of irradiation of cells that have incorporated melanin particles. Although these experiments have established the importance of laser-induced pressure waves as a cause of cellular injury, the characteristics and the magnitude of the generated pressure waves in situ were not known, so that no quantitative conclusions could be drawn.
Tissue and cell damage, induced by pressure waves from extracorporeal lithotriptors, have been extensively studied (e.g. Russo et al. 1987; Delius et al., Ultrasound Med. Biol. 14:117-122, 1988; Brauner et al., Ultrasound Med. Biol. 15:451-460, 1989; Cartensen et al., Ultrasound Med. Biol. 16:687-698, 1990; Gambihler et al., Ultrasound Med. Biol. 16:587-594, 1990; Brummer et al., J. Stone Dis. 4:243-248, 1992)). Brummer et al., (Ultrasound Med. Biol. 15:229-239, (1989)) have conducted a thorough study of the L1210 mouse leukemia cells in suspension subjected to pressure waves of up to 386 bar. Approximately 70% of the cells in the cultures subjected to this pressure were damaged after 1000 pulses. Cells immobilized in gels, under otherwise identical conditions, showed no histological damage and only minor decrease in viability. These experiments demonstrated that cavitation during irradiation was responsible for the cell damage. In a recent study Prat et al. (Cancer Research 51:3024-3029, (1991)) have administered gas microbubbles in order to increase the toxicity of the shock waves, showing that cavitation was the primary mechanism of cell injury.
Russo et al. (J. Urol. 135:626-628, (1986); J. Urol. 137:338-341, (1987)) exposed tumor nodules to pressure waves in vivo. The nodules did not show any histological changes. The treatment, however, caused retardation in the growth of the tumor. In addition, Carstensen and coworkers (Carstensen et al, Ultrasound Med. Biol. 16:687-698, 1990; Hartman et al., Ultrasound Med. Biol. 16:581-585, 1990) have demonstrated the effects of pressure waves on Drosophila larvae and chick embryos. They have shown that the number of deaths and malfunctions increased when chick embryos were subjected even to moderate pressure. Furthermore, in the latter experiments a membrane was used to separate the pressure wave from the cavitation. These experiments suggest that the observed biological effects may be induced by effects other than cavitation, e.g., pressure waves.
Several investigators have utilized the combination of pressure impulses and drugs. Holmes et al. (J. Urol. 144:159-163, 1990) describe the use of between 2000 and 4000 high pressure, short-duration pulse waves in combination with cisplatinum for the treatment of prostate tumors in rats. Although delayed tumor growth was achieved, an increase in animal mortality from 9% with cisplatinum alone to 29% with cisplatinum combined with shockwave therapy was observed. Berens et al. (J. Urol. 142:1090-1094, 1989) describe the use of spark-induced pressure impulses followed by therapy with several chemotherapeutic agents decrease tumor cell proliferation. Randazzo et al. (Urol. Res. 14:419-426, 1988) used several drugs followed significantly later by shock waves. This regimen produced enhancement with doxorubicin but not cisplatinumo Vivino et al. (Ultrasound Med. Biol. II:751-759, 1985) describe the use ultrasound and Russo et al. (J. Urol. 135:626-628, 1986) describe the use of a large number of shock waves alone to kill cells. Umemura et al. (Jpn. J. Cancer Res. 81:962-966, 1990) and Yumita et al. (Jpn. J. Cancer Res. 81:304-308, 1990) demonstrate the use of continuous wave ultrasound and hematoporphyrin to enhance tumor death.